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Cardiovascular Research Advance Access first published online on December 17, 2008
This version [Corrected Proof] published online on January 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvn351
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells

I.-Chung Lo1,2, Tsun-Mei Lin3,4, Ling-Hui Chou2, Shu-Lin Liu4,5, Li-Wha Wu1,4,6, Guey-Yueh Shi1,4,5, Hua-Lin Wu1,4,5 and Meei Jyh Jiang1,2,4,*

1 Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan, Republic of China
2 Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan, Taiwan, Republic of China
3 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan 70101, Taiwan, Republic of China
4 Cardiovascular Research Center, National Cheng Kung University College of Medicine, Tainan, Taiwan, Republic of China
5 Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan, Republic of China
6 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China

* Corresponding author. Tel: +886 6 2353535, ext. 5331; fax: +886 6 2093007. E-mail address: mjiang{at}mail.ncku.edu.tw

Aims: Thrombomodulin (TM), a potent anticoagulant, is not detected in quiescent vascular smooth muscle cells (VSMCs). In diseased vessels, VSMC expresses TM, but the mechanisms are unclear. This study examined molecular mechanisms for TM expression in VSMCs.

Methods and results: Platelet-derived growth factor-BB (PDGF-BB) induced TM expression in cultured human aortic VSMCs. PDGF-induced TM is functional in activating protein C. TM induction was eliminated by inhibitors of Src kinase, phosphatidylinositol 3-kinase (PI3-kinase), and mammalian target of rapamycin (mTOR) and by expressing dominant-negative Akt while expressing active Akt-stimulated TM expression. PDGF-BB activated the TM promoter, and the deletion of a sequence segment –394/–255 drastically reduced TM promoter activity. Transcription factor E26 transformation-specific sequence-1 (Ets-1) was upregulated by PDGF-BB in a PI3-kinase- and mTOR-dependent manner. RNA interference of Ets-1 inhibited PDGF induction of TM, and overexpressing Ets-1 increased TM expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay detected increased Ets-1 binding to the TM promoter after PDGF treatment. Following carotid artery ligation of C57/BL6 mice, PDGF-BB and TM were co-expressed in the media and neointima.

Conclusion: In VSMCs, PDGF-BB stimulates TM expression that is mainly mediated by Ets-1 via the Src kinase/PI3-kinase/Akt/mTOR signalling pathway. Furthermore, PDGF-BB may regulate TM expression in VSMCs during vascular remodelling.

KEYWORDS Thrombomodulin; Platelet-derived growth factor-BB; Vascular smooth muscle; Ets-1; Phosphatidylinositol 3-kinase

Time for primary review: 25 days


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